review article oxidative stress in radiation-induced...

Review ArticleOxidative Stress in Radiation-Induced Cardiotoxicity

Zhang Ping ,1 Yang Peng,2 Hong Lang,2 Cai Xinyong,2 Zeng Zhiyi,2 Wu Xiaocheng,2

Zeng Hong,2 and Shao Liang 2

1Department of Neurology, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, 330006 Jiangxi, China2Department of Cardiology, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, 330006 Jiangxi, China

Correspondence should be addressed to Shao Liang; [email protected]

Received 23 November 2019; Revised 3 January 2020; Accepted 13 February 2020; Published 2 March 2020

Academic Editor: Gianna Ferretti

Copyright © 2020 Zhang Ping et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

There is a distinct increase in the risk of heart disease in people exposed to ionizing radiation (IR). Radiation-induced heart disease(RIHD) is one of the adverse side effects when people are exposed to ionizing radiation. IR may come from various forms, such asdiagnostic imaging, radiotherapy for cancer treatment, nuclear disasters, and accidents. However, RIHD was mainly observedafter radiotherapy for chest malignant tumors, especially left breast cancer. Radiation therapy (RT) has become one of themain ways to treat all kinds of cancer, which is used to reduce the recurrence of cancer and improve the survival rate ofpatients. The potential cause of radiation-induced cardiotoxicity is unclear, but it may be relevant to oxidative stress. Oxidativestress, an accumulation of reactive oxygen species (ROS), disrupts intracellular homeostasis through chemical modification anddamages proteins, lipids, and DNA; therefore, it results in a series of related pathophysiological changes. The purpose of thisreview was to summarise the studies of oxidative stress in radiotherapy-induced cardiotoxicity and provide prevention andtreatment methods to reduce cardiac damage.

1. Introduction

Radiotherapy plays an important role in the treatment ofmany cancers. As the use of radiotherapy is becomingincreasingly frequent, and since the overall patient survivalrate is high, the risks associated with radiotherapy must becarefully considered. Among these risks, cardiovascular dis-eases (CVDs) have always attracted much attention, sinceCVD is the leading cause of nonmalignant tumor-relateddeaths in cancer survivors [1].

In a clinical setting, gamma rays and X-rays are the mostcommonly used types of ionizing radiation. Radiation-induced cardiotoxicity depends on the type and dose of radi-ation [2]. Clinical studies have shown that a radiation dose of1–4Gy promotes the development of CVD and inflamma-tion [3]. A radiation dose of 5–8Gy increases the possibilityof myocardial infarction (MI), angina, pericarditis, anddecreased left ventricular diameter, while radiation doses ofmore than 8Gy cause myocardial fibrosis, which usuallyoccurs after irradiation for Hodgkin’s lymphoma (HL)[4–6]. At doses above 30Gy, the risk of radiation-related

heart disease becomes significant if the patient is exposed fora year or two; however, the latent period of radiation-relatedheart disease is longer and disease can occur more than afew decades later if exposure has been at lower radiation doses[7]. Studies have shown that in an experiment with a larger-than-average cardiac radiation dose, the risk of heart deathincreased significantly by approximately 3% per Gy of radia-tion dose [2, 7]. Radiotherapy is now used for approximatelyhalf of all malignant tumors and is the basic treatment forHL and breast cancer [8]. Nevertheless, radiation-inducedcoronary heart disease is the second most common cause ofmortality and incidence in patients with breast cancer andHL treated with radiotherapy [9]. The use of high doses ofradiation in the treatment of cancer has been shown todamage heart tissue, leading to cardiac dysfunction andCVD [2]. The available data show that the higher the radi-ation dose, the stronger is the cardiotoxicity, and the riskof cardiovascular complications is also increased. Moreover,the risk of cardiovascular complications in patients whoreceived radiotherapy for left breast cancer was significantlyhigher than the risk in patients who received radiotherapy

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for right breast cancer [10]. Although the benefit of radio-therapy is obvious, increasing attention has been paid to thecardiac damage induced by radiotherapy, which would sug-gest limiting the dose and use of radiotherapy in cancerpatients [11]. Modern radiotherapy techniques may not havedecreased cardiac toxicity even though they have reduced theexposure of the heart to radiation [12]. A number of studieshave emphasized the role of oxidative stress and inflamma-tion in radiation-induced cardiovascular damage and haveshown that most chemotherapeutic drugs and radiotherapycan increase oxidative stress. Therefore, antioxidative stresshas become an important therapeutic target for radiation-induced cardiotoxicity.

Chest radiotherapy is used to effectively treat somemalignant tumors, such as HL and breast cancer. However,the incidence of cardiovascular events in these patients hasincreased for years, especially among young survivors whodo not have traditional risk factors [13]. Oxidative stress incells is the main factor of CVD [14]. Oxidative stress repre-sents the imbalance between the production of reactiveROS and the scavenging of ROS by the cell antioxidantdefense system, thus, mediating the damage of cell structure,including lipids, proteins, and DNA [15]. Oxidative stressand ROS production have always been considered to beimportant pathophysiological mediators leading to CVD.Chronic and acute overproduction of ROS under pathophys-iological conditions is an important part of the developmentof CVD [16]. In general, there is a considerable amount ofdata indicating that oxidative stress and ROS are related tothe pathophysiology of CVD [17]. The effect of oxidativestress on radiation-induced cardiotoxicity may be mainlyowing to the oxidative damage of biological macromolecules(DNA, protein, and lipids) and a series of molecular signalingpathways mediated by ROS through the excessive productionof ROS.

1.1. Formation of ROS. As illustrated in Figure 1, oxidativestress refers to the imbalance between oxidants and antioxi-dants, which is favorable to oxidants and leads to harmfuleffects [15]. Oxidants, also known as ROS, include superox-ide radical anions (O2

-), hydrogen peroxide (H2O2), hydroxylradical (OH-), and singlet oxygen. In addition, they alsocontain some nitrogen oxides, lipid peroxide free radical(LOO), and hypochlorous acid (HOCl) [14, 18]. ROS in thecardiovascular system come from endogenous sources, suchas NADPH oxidases, mitochondria, xanthine oxidases,cyclooxygenase (COX), lipoxygenase (LPO), and uncouplednitric oxide synthases (NOSs); exogenous sources of ROSinclude chemical toxins, radiation, ultraviolet rays, cigarettesmoke, and drugs. These sources result in elevated ROSconcentrations and subsequent cardiovascular tissue damage[14, 19]. Mitochondria are the major sites of intracellularoxygen consumption, and the respiratory chain of mitochon-dria is the main source of ROS, which has an important effecton the cardiovascular system [20]. IR can directly cause therespiratory chain of mitochondria to breakup, leading torespiratory chain dysfunction and thus reducing ATP pro-duction, increasing ROS production, reducing antioxidantcapacity, and inducing apoptosis [21]. NADPH oxidase

(NOXs) is the main enzymatic source of ROS in the cardio-vascular system [22]. Among them, NOX2 and NOX4 arethe most abundant in the heart and are expressed in cardio-myocytes and endothelial cells. These enzymes catalyze thetransfer of electrons from NADPH to oxygen molecules toproduce oxygen free radicals [23]. In addition, the late effectsof radiation therapy are caused by the ionization of watermolecules in the surrounding environment and the genera-tion of chronic free radicals induced by radiation [24]. Radi-ation can not only change the upstream source of ROS butalso change the balance of endogenous antioxidant defensemechanisms, including glutathione, ascorbic acid, catalase,and superoxide dismutase (SOD) [25]. The inhibition of anti-oxidant enzymes is one of the important effects of ionizingradiation on irradiated organs and off-site organs, whichleads to the production and accumulation of ROS [26].ROS can react randomly with cellular lipids, proteins, andnucleic acids, and cause oxidative stress, thus damaging thesemacromolecules [25].

1.2. ROS-Mediated Oxidative Damage to Biomacromolecules.ROS are a kind of small reaction molecule and play a key rolein regulating cell function and biological process [27]. ROSare highly reactive and can interact with biological macro-molecules, such as DNA, proteins, and lipids, and can pro-duce various pathological manifestations via changing thefunction of these macromolecules [15].

1.2.1. DNA Oxidation. Radiation directly and indirectlyaffects heart tissue. Radiation may interact directly withDNA and cause DNA damage [28]. The ROS produced bythe radiation decomposition of water molecules and the sur-rounding DNA molecules are considered the indirect effect[29]. The IR-induced DNA damage is mainly caused by indi-rect effects, including base damage, cross-linking, single-strand break (SSBS), and double-strand break (DSBS). Inthese lesions, they can be either alone or in combination withanother, resulting in complex DNA damage, with DSBSbeing the most severe [30]. The oxidative damage of DNAcan change gene expression, resulting in protein modifica-tion, cell death, and genome instability [29]. The mitochon-drial respiratory system is the main source of ROS in cells.They are by-products of the transfer of electrons fromNADH or FADH to molecular oxygen under normalphysiological conditions, and these toxic by-products aretreated by antioxidants and free radical scavenging enzymes,including manganese superoxide dismutase (Mn-SOD),catalase (CAT), and glutathione peroxidase (GPX) in mito-chondria [31]. However, owing to the lack of chromatin struc-ture, histone protection, and an inefficient repair system,mtDNA is vulnerable to oxidative stress-related damage. Ifnot repaired, it will lead to the destruction of the electronictransport chain and produce more ROS, which exceeds theprotective ability of the antioxidant system [20, 31]. Reactiveoxygen-induced mitochondrial DNA oxidative damage andmitochondrial damage lead to the pathological productionof ROS, and the formation of the vicious cycle leads tocell energy consumption and apoptosis. The accumulationof mitochondrial DNA oxidative damage can lead to

2 Oxidative Medicine and Cellular Longevity

mitochondrial dysfunction, which is an important causeof some human diseases, including CVD [20].

1.2.2. Protein Oxidation. Oxidative stress by ROS producedafter radiation can lead to chain breaks, protein chargechanges, protein cross-linking, and oxidation of specificamino acids, resulting in increased susceptibility to a partic-ular protease-degrading protein. Cysteine and methionineresidues in the protein are particularly sensitive to oxidation.The oxidation of the base or methionine residue can causeconformational change, protein expansion, and degradation[15]. Oxidative stress-induced protein oxidative modificationbefore protein degradation or inactivation increased. A pre-vious study has shown that homocysteamine was commonin irradiated endothelial cells, and the increased level ofhomocysteine was associated with various human CVDs,including atherosclerosis [32]. Oxidative damage of proteinsin vivo may affect the function of receptors, enzymes, trans-porters, etc., and cause secondary damage to other biomole-cules [33]. As one of the main protein targets of ROS,Ca2+/calmodulin-dependent protein kinase II (CaMKII)plays a key role in the pathophysiology of CVDs [34].CaMKII is a serine-threonine kinase. There are four knownsubtypes: α, β, γ, and δ. δ subtypes play a dominant role inthe heart. CaMKII is activated not only by binding calcium-bound calmodulin (Ca2+/CaM) but also by oxidation [35].The oxidation of CaMKII is carried out by ROS, and in thepresence of ROS, methionine 281 and 282 in CaMKII are oxi-dized [36]. In the domain of Ca2+/CaM-binding CaMKII,

oxidation of M281/282 leads to enzyme activation whichinhibits the recombination between a regulatory subunitand a catalytic subunit, thus perpetuating the activity ofCaMKII [34]. The effect of CaMKII enhanced by oxidationis complex and widely present in the cardiac muscle cells,and the excessive activation of CaMKII may be related to car-diomyopathy and abnormal excitation-contraction coupling(ECC), heart failure, and arrhythmia [35, 36].

1.2.3. Lipid Peroxidation. The main mechanisms for freeradical-induced cell and tissue damage include the formationof lipid peroxides in the cell membrane and organelles. Thisprocess begins when the free radical is extracted from poly-unsaturated fatty acids (PUFA) to form a fatty acid radical.The biologically active lipid peroxidation radical can reactwith other lipids, proteins, or nucleic acids to facilitate thetransfer of electrons and the oxidation of the substrate. Theseorganic radicals perpetuate the chain reaction by attackingadditional side chains, resulting in the formation of a lipidperoxide [37]. In general, lipid peroxide can be described asthe process of oxidants (such as free radicals) attacking lipidscontaining carbon double bonds, especially PUFA [28].PUFA, in particular linoleic acid and arachidonic acid, arean important target of lipid peroxide. Malondialdehyde(MDA) and 4-hydroxy-2-non-ene (HNE) are the mostimportant products of lipid oxidation [21]. ROS can inducelipid peroxide and destroy the bilayer arrangement ofmembrane lipids, which may lead to the inactivation ofmembrane-binding receptors and enzymes and increase the

Radiation

Respiratory chain H20

NADPH

NADPH

NADPH

PGH2COX-2

5-LPO

ROSUncoupledNOS

Xanthine

XanthineoxidaseUric acid Arachidonic

acid

oxidaseNADP+

DNA, protein lipid oxidation

Pericardialdisease

Coronary heartdesease

Valvular heartdesease

Conductiondysfunction

Cardiomyopathy

Molecular signalingpathway

NADP+

breakup

Figure 1: Formation of ROS after radiation and the general manifestation of cardiotoxicity. As described in the article, the sources of ROS arevaried, even under the radiation conditions. IR can directly cause the respiratory chain of mitochondria to breakup and cause thedecomposition of water molecules, leading to respiratory chain dysfunction and ROS production, reducing antioxidant capacity. NADPHoxidase is a family of multisubunit complex enzymes that catalyze the conversion of oxygen into O2

- by using NADPH as an electronsource, which is present in vascular endothelia cells, smooth muscle cells, fibroblasts, and cardiomyocytes. The mechanism of uncoupledNOSs is similar to NADPH oxidase. Xanthine oxidase catalyzes the conversion of xanthine to uric acid while H2O2 and O2

- are generatedat the same time. In addition, COX-2 and 5-LPO produce PGH2 accompanied by ROS formation during catalytic arachidonic acidmetabolism. ROS can interact with macrobiomolecules (DNA, protein, and lipid), causing oxidation of DNA, proteins, and lipids andcause cardiac damage through some signaling pathways, which are described in article above. The cardiac damage includes pericardialdisease, coronary heart disease, heart valve disease, conduction disorders, and cardiomyopathy.

3Oxidative Medicine and Cellular Longevity

permeability of tissues. Lipid peroxidation products, such asMDA and unsaturated aldehyde, can inactivate many cellproteins by forming protein cross-linking. HNE can lead tointracellular glutathione (GSH) depletion and induce perox-ide production, activate epidermis growth factor receptor,and induce fibronectin production [15]. Because the myocar-dial cell membrane is rich in phospholipids which are partic-ularly sensitive to oxidative stress and the antioxidantcapacity is low, the myocardium is particularly vulnerableto oxidative damage of free radicals produced by ionizingradiation. Lipid peroxidation in the myocardial cell mem-brane can lead to injury of the myocardial structure andimpaired function [38]. In addition, lipid peroxide also existsin the oxidation of low-density lipoprotein (LDL) [28]. Ath-erosclerosis is the pathological basis of coronary heart diseaseand is closely related to oxidative LDL. Infiltration and accu-mulation of low-density lipoprotein cholesterol (LDL) in theendothelial cells occur after endothelial injury. Monocytesdifferentiate into macrophages and express scavenging recep-tors (SRS), such as CD36, SRA, and LOX-1 [27]. OxidizedLDL (OxLDL) attracts macrophages directly and is phago-cytic by macrophages. Because OxLDL is resistant to macro-phage lysosomal acidic proteolytes, the OxLDL collected bymacrophages is not digested and decomposed by macro-phages. Over time, OxLDL accumulates more and more inmacrophages and converts macrophages into cells contain-ing a lot of fat in cytoplasm, called foam cells [19]. In addi-tion, ROS induces the expression of SRS in smooth musclecells and converts them into foam cells. The presence of foamcells in the arterial wall is a sign of early atherosclerosis. Var-ious studies have shown that OxLDL can induce endothelialcells, vascular smooth muscle cells, and macrophages to pro-duce ROS, and ROS and cytokines released by inflammatorycells may stimulate smooth muscle cell migration andcollagen synthesis, leading to the formation of atheroscleroticplaques [27].

1.3. Molecular Signaling Pathway of Cardiac ToxicityMediated by ROS. Irradiation of normal tissues can lead toa sharp increase in ROS and reactive nitrogen species(RNS), which include nitric oxide (NO), nitrogen dioxide(NO2), and peroxynitrite (ONOO-). ROS/RNS are free radi-cals which are associated with the oxygen atom (O) or theirequivalents and have stronger reactivity with othermolecules.ROS/RNS as intracellular and intercellular signals change thefunction of cells and tissues [39]. In the case of chest irradia-tion, exposure of the heart, blood vessels, and other tissuesleads to tissue remodeling and adverse cardiovascular events.This complex process is composed of a large number of inter-acting molecular signals, including cytokines, chemotacticfactors, nuclear transcription factors, and growth factors [28].

1.3.1. TGF-β1 and Oxidative Stress. As shown in Figure 2,radiation-induced vascular injury and endothelial dysfunc-tion are partly mediated by transforming growth factor-(TGF-) β, which plays a key role in radiation-induced fibrosis[40]. ROS produced by radiation is an immediate activatingagent of TGF-β1, and the activated TGF-β1 initiates anupregulation of collagen synthesis in a dose-dependent

manner [41]. ROS can result in TGF-β1 activation, thrombinproduction, platelet activation, and proinflammatory signalactivation to promote myofibroblast accumulation and extra-cellular matrix (ECM) production. ROS is activated througha forward feedback loop by TGF-β1 to amplify these fibrosissignals. Radiation-induced ROS release TGF-β1 togetherwith ECM, causing oxidative damage to DNA, proteins,and lipids [42]. TGF-β1 activates two signal pathways, theSmad pathway and the TAK1/MKK3/p38 pathway, througha special nuclear signal transducer molecule called TRAF6.Collagen synthesis is controlled by these two pathways inthe steady state [42, 43]. In the classical signaling pathway,TGF-β recruits a complex of Type I (TbRI) and Type II(TbRII) transmembrane receptors to induce the phosphory-lation of Smad protein and induce the accumulation of Smadprotein in the nucleus to regulate the expression of targetgenes [44]. Many inflammatory cytokines, especially IL-6and IL-8, are involved in the Smad pathway, which mediatecollagen synthesis and lead to rational fibrosis and dysfunc-tion in heart disease. TAK1/MKK3/p38 signal transductionis the key to autophagy-dependent collagen degradation.TGF-β1 can also reduce the synthesis of proteolytic enzymesand increase the synthesis of protease inhibitors to degradematrix and downregulate autophagy-mediated collagen deg-radation, which may further promote TGF-β1-related events[42]. Radiation-induced coronary heart disease (RICHD) is alate effect of radiation exposure, with tissue fibrosis as thecommon end point. Fibrosis of the coronary and carotidarteries may destroy the normal blood supply of the heartmuscle, leading to ischemia and heart failure [30].

1.3.2. IGF-1 and Oxidative Stress. Insulin-like growth factor-1(IGF-1) is a primary mediator of the effects of growth hor-mones and is itself structurally similar to insulin [45]. Theassembly structure of the IGF-1 receptor (IGF-1R) is thesame as that of the insulin receptor, and the homology ofkinase domain β is more than 80%. Therefore, IGF-1 andinsulin have at least two main signal transduction pathways(PI3K-dependent and PI3K-independent pathways) throughtheir homologous receptor and cross-activation [46]. Amongthem, the most important cardiovascular function ofIGF-1 comprises the two main ways of regulating vasculartension: through the anti-inflammatory/antioxidant stressIRS/PI3K/Akt pathway and through the proinflammatoryand oxidative stress Grb/Shc/MAPK (PI3K-independent)pathway [47]. The activation of the IRS/PI3K/Akt pathwayleads to eNOS phosphorylation of Ser1179 and the pro-duction of nitric oxide (NO) within minutes. In the pres-ence of BH4, eNOS produces NO during the conversion ofL-arginine to L-citrulline. In the absence of BH4, eNOSuncoupling catalysis forms a superoxide instead of NO[17]. NO, a powerful vasodilator with antithrombotic andanti-inflammatory characteristics, is involved in oxidativestress and chronic endothelial activation and inflammation[48]. NO has an important protective effect on maintainingnormal cardiovascular function. Excessive ROS productioncan reduce the bioavailability of NO, which is the main factorfor the occurrence and development of CVDs [49]. Forexample, the activation of NF-κB after radiation is inhibited


by NO, and therefore, a decrease in the bioavailability of NOmay promote the development of vascular inflammation andatherosclerosis [40]. IGF-1 stimulates the expression ofendothelin-1 (ET-1) by activating the Shc/Grb/MAPKpathway via IGF-R, IR, or a hybrid receptor [17]. ET-1 is apowerful vasoconstrictive peptide secreted by endothelialcells. It can antagonize the vasodilation effect of NO andhas the characteristics of promoting oxidation and inflam-mation [50]. Research on mice has shown that IGF-1 pro-vides radiation protection, and the use of IGF-1 inhibitorsenhances the sensitivity of cancer cells to radiotherapy [51].As demonstrated by Kenchegowda et al. in 2018, IGF-1 levelswere increased in irradiated minipigs but a positive correla-tion was observed between elevated IGF-1 levels after radia-tion and cardiac adverse events. It was further proven thatthe IGF-1/PI3K/Akt pathway was inhibited while the MAPKpathway remained active, resulting in the transformation ofthe IGF-1 signal to an oxidative and proinflammatoryenvironment, which led to selective resistance of IGF-1[45]. Furthermore, other pathological stimuli such as ROSand inflammatory cytokines can cause selective inhibitionof the IRS/PI3K/Akt pathway and even enhance the MAPKsignal pathway [47]. Selective IGF-1 resistance has recentlybeen considered to be a new radiation injury mechanismrelated to inflammation and endothelial dysfunction [52].The inhibition of the IRS/PI3K/Akt/eNOS signal transduc-

tion pathway and the activation of the Grb/Shc/MAPK/ETpathway lead to an imbalance between NO and ET-1, result-ing in endothelial dysfunction and CVD [47]. Endothelialdysfunction refers to a complex pathological state, which ischaracterized by a series of events, including damage of theendothelial barrier, damage of vasodilation and contraction,decrease of NO production, increase of adhesion moleculeexpression, increase of cytokine levels, and ROS producedby endothelial cells. Endothelial dysfunction helps promotefibrosis and an inflammatory environment, leading to fibro-sis as a secondary effect, which is a common feature ofradiation-induced tissue damage [32]. The injury of vascularendothelial cells plays an important role in radiation-inducedheart injury [48]. The overall results of IGF-1 resistanceinclude vasoconstriction, decrease of blood flow, hypoperfu-sion, and a further increase of oxidative stress, which leads tothe increase of ROS level and the formation of a vicious cycle.ROS can promote the inhibition of the PI3/Akt pathway,decrease the bioavailability of NO, and induce the productionof ET-1, leading to vascular dysfunction, inflammation, andthrombosis, and ultimately to the occurrence and develop-ment of atherosclerosis [45]. Moreover, endothelial injury isoften accompanied by myocardial injury, which results incollagen deposition in the capillary cavity, stenosis ofblood vessels, and deterioration of myocardial blood supply,forming a vicious cycle of myocardial blood supply and

Platelet activation

ROSRadiation

TAK1/MKK3/p38 SMAD2/3

TRAF6

IL-6, IL-8

Collagen synthesis

AutophagyCollagen degradation

Fibrosis environment

Atheroscierosis and ischemic heart disease

Heart failure

TGF-𝛽1

Figure 2: Oxidative stress in TGF-β1-mediated fibrosis. Radiation induces reactive oxygen species (ROS), and ROS can activate TGF-β1,resulting in the generation of thrombin and the activation of platelets to promote further production of ROS and TGF-β1. TGF-β1 bindsto Type I (TbRI) and Type II (TbRII) transmembrane receptors, activating the Smad pathway and the TAK1/MKK3/p38 pathway throughthe specific nuclear signaling transduction molecule, TRAF6. The Smad pathway requires a number of inflammatory cytokines, inparticular IL-6 and IL-8, to mediate collagen synthesis. TGF-β1 activates the TAK1/MKK3/p38 signaling pathway and downregulatesautophagy-mediated collagen degradation, which may further promote the synthesis of collagen, form a fibrotic environment, causeatherosclerosis and ischemic heart disease, and may even lead to heart failure.


continuous fibrosis and remodeling [53]. This process isdescribed in Figure 3.

1.3.3. NF-κB and Oxidative Stress. As shown in Figure 4, ROSform an important intermediate and second messenger acti-vated by NF-κB through upstream stimuli, such as tumornecrosis factor (TNF) and interleukin-1 (IL-1) [54]. NF-κBbelongs to the family of inducible transcription factors.NF-κB regulates different biological processes, includingimmune response, inflammation, cell proliferation, and apo-ptosis. NF-κB binds to inhibitor protein IKB (IκBα, in partic-ular, has been extensively studied) to form protein complexesand remains inactive [28]. When cells are exposed to ionizingradiation, oxidative stress occurs rapidly. The activation of theTNF receptor and the IL-1 receptor, the upstream receptors ofthe typical signaling pathway of NF-κB, further activates theIKK complex (primarily IKKβ) composed of IKKα and IKKβ(catalytic kinase), which phosphorylates IκBα on serines 32and 36, resulting in the phosphorylation and degradation ofIKB protein and the activation and translocation of NF-κBto the nucleus [55]. It can bind to various promoter regionsof its target genes and induce transcription of correspondinggenes, most of which are involved in the regulation ofinflammation [28, 56]. NF-κB target genes include COX-2and 5-LPO, and these two are the sources of ROS generation.5-LPO, similar to COX-2, produces prostaglandin H2(PGH2) accompanied by ROS formation during catalytic ara-chidonic acid metabolism, and intracellular ROS productioncan directly activate NF-κB [55]. Therefore, a positivefeedback loop can be formed between NF-κB and ROS. ROS

activates NF-κB, which in turn increases the production ofROS by increasing the expression of COX-2 and 5-LPO[19]. In addition, NF-κB is activated by oxidative stress afterradiation, which targets the production of many genes relatedto inflammation, including intercellular adhesion molecules(ICAM), vascular cell adhesionmolecules (VCAM), and cyto-kines, and promotes the upregulation of thrombus formationmarkers [40]. Furthermore, NF-κBupregulates the expressionof cytokines such as IL-1 and TNF. These cytokines increaseinflammation not only by attracting white blood cells but alsoby activating NF-κB [57, 58]. Thus, the inflammatory state ofatherosclerosis may again form a positive self-regulatory loop[19]. This proinflammatory environment, coupled with colla-gen deposition and increased fibroblasts, leads to tissueremodeling, myocardial fibrosis, and atherosclerosis, whichis one of the end-stage symptoms of radiation-induced heartdisease [54]. In addition, the inflammation regulated byNF-κB is also associated with myocardial injury inducedby radiation. Because of the increased expression of intercelladhesion molecules and vascular cell adhesion molecules, theadhesion of leukocytes to the endothelial cells and the throm-bus can prevent the vascular cavity from causing micro-thrombus and vascular occlusion, thereby causing fillingdefects and focal ischemia, followed by further myocardialcell death and fibrosis [28].

1.3.4. IL-4 and Oxidative Stress. IL-4 has long been consid-ered to be an effective fibrogenic factor because it can inducethe synthesis of ECM protein, collagen, and fibronectin [59].Recent studies have shown that IL-4 and IL-13 are of

Radiation

ROS IGF-1

IGF-R/1R

GrbIRS

P13K

AKT

NO

Endothelial dysfunction

RIHDInflammationoxidative stress

Shc

MAPK

ET-1

Figure 3: Radiation induced IGF-1 selective resistance. Insulin-like growth factor-1 (IGF-1) is structurally similar to insulin. It can activatethe IRS/PI3K/Akt pathway (PI3K dependent) and the Grb/Shc/MAPK pathway (PI3K independent) through IGF-R, IR, or the hybridreceptor. However, radiation can inhibit the anti-inflammatory and antioxidant stress of the IRS/PI3K/Akt signaling pathway but notinhibit the inflammatory MAPK kinase pathway, which leads to the transformation of the IGF-1 signal to the oxidation and inflammatoryenvironment, which leads to selective resistance of IGF-1. ROS can also cause selective inhibition of IRS/PI3K/Akt pathway and evenenhance the MAPK signaling pathway. IGF-1 selective resistance causes an imbalance between NO and ET-1 production, resulting inendothelial dysfunction, resulting in oxidative stress and inflammatory level and further leads to the occurrence and development ofradiation-induced heart diseases.


importance in the late cardiac effects induced by ionizingradiation [60]. IL-4 and IL-13 are mainly secreted by Th2lymphocytes and act on a variety of tissues to stimulatecollagen synthesis [61]. These cytokines may induce chronicoxidative stress, inflammation, and fibrosis by upregulatingdual oxidase 1 (DUOX1) and dual oxidase 2 (DUOX2).DUOX is also known as an NADPH oxidase, one of the mainsources of ROS [60]. DUOX1 and DUOX2 are twomembrane-dependent subfamilies of oxidoreductase, whichcatalyze the conversion of oxygen (O2) to hydrogen peroxide(H2O2). The two enzymes are very similar and can produce alarge amount of H2O2 after activation. The abnormal upreg-ulation of these enzymes may lead to the destruction of nor-mal function and the increase of oxidative damage [62].Chronic oxidative stress and inflammation can lead to fibro-sis and hypertrophy, which may undermine normal cardiacfunction and myocardial blood supply [63]. A study byFarhood et al. in 2017 showed that irradiation increased thelevel of IL-4 but not the level of IL-13 in rats. The results ofreal-time PCR showed that radiation induced the upregula-tion of IL4ra1 (IL-4 receptor), DUOX1, and DUOX2; thechanges induced by IL4ra1 and DUOX1 were the most obvi-ous [62]. In addition to DUOX1 and DUOX2, IL-4 can also

induce the upregulation of TGF-β, a powerful stimulator offibrosis [63]. As mentioned earlier, the activation of theTGF-β pathway mediates collagen synthesis, promotes tissuefibrosis, and plays an important role in late radiation-induced cardiac toxicity.

1.4. Clinical Manifestations of Radiation-InducedCardiotoxicity. The use of high doses of radiation in cancertreatment has been shown to damage heart tissue, leadingto cardiac dysfunction and CVD [2]. Radiation-inducedCVDs can include pericardial disease, coronary artery disease,valvular heart disease, conduction disease, and cardiomyopa-thy [8, 13]. Heart disease caused by radiotherapy developsslowly and occurs 20–30 years after radiotherapy [24].

1.4.1. Radiation-Induced Pericardial Disease. Pericardial dis-ease is a common and classic complication of mediastinalradiotherapy; its types include acute pericarditis, pericardialeffusion, delayed thickening, and constrictive pericarditis[13]. In a postmortem study, 20 cancer patients with a historyof mediastinal radiotherapy were examined. 70% (14) of thepatients had pericardial disease, the most common of whichwas exudative or constrictive disease [64]. The symptoms of

RadiationROS

IL-1

IL-1 receptor

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TNF receptor

Mitochondrialelectron transport

NADPH

NADPH

NADP+I𝜅B𝛼 degradedROS

NF-𝜅BNF-𝜅B

NF-𝜅B

Gene expression

Arachidonic acidmetabolism

COX-2

5-LPO

IL-1TNF

InflammationAtherosclerosis

ICAM

VCAM

oxidasesI𝜅B𝛼

Figure 4: The relationship between oxidative stress and NF-κB. In normal cases, NF-κB combines with the inhibitor protein (IKB) to form aprotein complex and remain in an inactive state. However, when the cells are exposed to ionizing radiation, oxidative stress reactions, such asNADPH oxidase activity, improved and mitochondrial electron transport is impaired and occurs rapidly, and reactive oxygen species isexcessively generated in response to oxidative stress, which stimulates the inflammatory cells to produce IL-1 and TNF. IL-1 and TNFbind to the IL-1 receptor and the TNF receptor, respectively, to activate the downstream NF-κB signal. The IKB protein is phosphorylatedand NF-κB is activated and translocated to the nucleus, which binds to the various promoter regions of its target gene and induces thetranscription of a corresponding inflammation-related gene. The activated NF-κB induced the expression of COX-2 and 5-LPO, resultingin the generation of ROS, the formation of a positive feedback loop, and increased levels of inflammation and oxidative stress, and theintracellular ROS can activate NF-κB directly. In addition, the activation of NF-κB also results in an increase in the expression ofintercellular adhesion molecules (ICAM) and vascular cell adhesion molecules (VCAM). In addition, NF-κB upregulated the expression ofcytokines such as IL-1 and TNF. These cytokines increase inflammation not only by attracting white blood cells but also byactivating NF-κB. Thus, the inflammation state of atherosclerosis may again form a positive self-regulatory loop, forming proinflammatoryand fibrotic environments, leading to tissue remodeling, myocardial fibrosis, and atherosclerosis.


these patients developed at different times and appearedthree to five years after radiation [13]. Acute pericarditis usu-ally occurs during radiotherapy or within a few weeks afterradiotherapy, and the exudate is fibroid. It is usually causedby high-dose (40Gy) radiation therapy for mediastinaltumors, especially HL [40]. However, acute pericarditis isnow rare owing to new radiotherapy techniques, such as deepinspiratory breath-holding (DIBH) and accelerated partialbreast irradiation (APBI), which significantly reduce the doseof cardiac radiation exposure [62, 65]. The patients couldshow fever, pleurisy and chest pain, abnormal electrocardio-gram, and slight elevation of cardiac markers. The disease isusually self-limited and effectively treated by nonsteroidalanti-inflammatory drugs (NSAID) and colchicine [62].Radiation-induced chronic pericarditis often has no relativesymptoms, but it can be disguised as angina or it couldcoexist with angina [9]. It is important to note, however,that chronic pericardial diseases can develop months toyears after radiotherapy treatment and may lead to largepericardial fluid accumulation. Excessive accumulation maylead to pericardial tamponade. Symptoms and signs, suchas dyspnea, accompanied by distal heart sound, hypotension,and a dilated jugular vein, may be diagnostic indicators.Echocardiography is still the golden standard for determinis-tic diagnosis [53]. Constrictive pericarditis is usually one ofthe most serious complications, and diuretics are usuallythe first line of defense; however, the final treatment ispericardiectomy [8, 13].

1.4.2. Radiation-Induced Coronary Heart Disease. RICHD isthe second most common cause of onset and death inpatients with breast cancer, HL, and other common medias-tinal malignant tumors. The risk of RICHD increases withthe increase of the radiation dose. Exposed patients maydevelop a variety of symptoms after decades of treatment,including asymptomatic myocardial perfusion defects, sto-matal processes, triple-vessel disease, and sudden cardiacdeath [9]. In terms of pathology, RICHD and common coro-nary heart disease differ in some respects. RICHD lesionstend to be long, preferentially affecting the ostial area of thecoronary arteries, and the collagen and fibrin content in theformed inflammatory plaques are high and the fat contentis low [62]. Acharya et al. in 2018 studied a case of coronaryartery disease caused by radiotherapy for breast cancer andfound severe, isolated bilateral coronary artery orifice lesions[66]. The typical manifestation of RICHD is that youngpatients with typical angina symptoms do not have risk fac-tors for ischemic heart disease, and coronary artery occlusioninvolves more frequently the coronary artery opening andproximal coronary artery segment than the distal coronaryartery segment [9, 48]. Although there are few traditionalcardiovascular risk factors in patients with radiation coro-nary heart disease, if such risk factors such as hyperlipidemiaexist, the progress of atherosclerosis might be accelerated[66]; and even though angina symptoms are common inpatients with RICHD, nonanginal chest pain is the mostcommon in the first 2–3 years after chest irradiation and/ormastectomy, accounting for approximately 50% of breastcancer survivors [9]. Patients with radiation coronary heart

disease have a higher risk of asymptomatic myocardialinfarction than the general population. The treatment ofradiation-induced coronary artery disease, however, is nodifferent. Cardiac surgery, including angioplasty, stenting,or bypass grafting may be used, but it may be more techni-cally difficult and the procedure is more complex [67].

1.4.3. Radiation-Induced Valvular Heart Disease. Early heartvalve injury caused by radiation is usually manifestedthrough the thickening and calcification of the valve and lob-ule. These abnormalities rarely show clinical symptoms, butin imaging studies, the detection rate of valvular lesions was60% and it was as high as 80% in autopsies [67]. Radiation-induced valvular disease can develop from intimal thicken-ing, no dysfunction to asymptomatic valvular dysfunction,and eventually symptomatic valvular stenosis or regurgita-tion [48]. Radiotherapy was found to increase the clinical riskof severe valvular disease, especially when the dose is above30Gy, with aortic valve involvement being the most frequent[68]. Aortic regurgitation is the most common valvular dis-ease, but most patients show mild valve injury [13]. Aorticand mitral valves are more likely to be involved than tricus-pid and pulmonary valves [8]. Valvular stenosis can occur20 years after radiotherapy, and aortic stenosis is the mostcommon type when valvular stenosis occurs [62]. Echocardi-ography has shown abnormal calcification of aortic inter-valvular fibers and of the anterior mitral valve in patientswith mild valve injury. Heart souffle and echocardiographysuggest that valvular disease should be examined by echocar-diography on a regular basis. Surgical treatment should beconsidered for patients with severe valvular disease [8].

1.4.4. Radiation-Induced Conduction Dysfunction. Radio-therapy may affect the conduction system of the heart, lead-ing to various types of arrhythmias [69]. The conductionsystem after radiation is rarely involved, but the range ofthe electrocardiogram after irradiation shows prolongednonspecific ST-T, QT interval, decreased voltage, rightbundle branch block, and sinus tachycardia [48]. Commonconduction disorders occur quickly after radiation, includingnonspecific repolarization changes, which are usually tran-sient and asymptomatic, while severe abnormalities includ-ing atrioventricular node bradycardia, all levels of cardiacblock, and sick sinus syndrome are known to occur manyyears after radiotherapy [48]. The abnormality of the con-duction system may be caused directly by radiation or indi-rectly by the fibrosis and ischemia of the myocardiumcaused by radiation therapy, in which the right bundlebranch block is most common because the right bundlebranch is located in the vicinity of the endocardium and ismost likely to be damaged during radiotherapy [48]. Com-plete heart block is a serious and delayed manifestation ofradiation-induced cardiac damage, requiring pacemakerimplantation [8, 13].

1.4.5. Radiation-Induced Cardiomyopathy.Myocardial injuryafter radiation is related to microvascular injury, such asthe decrease of microvessel density, the loss of alkalinephosphatase in vascular endothelial cells, and the increased


expression of von Willebrand factor. Acute myocarditisis associated with inflammation caused by radiotherapy,accompanied by transient ST, T wave electrocardiogramabnormalities, and myocardial dysfunction [8]. Myocardialfibrosis induced by radiotherapy develops through the separa-tion and replacement of proliferating collagen from the cardi-omyocytes, whichmay lead to ischemic heart disease and evenheart failure [2]. Myocardial fibrosis usually develops when apatient is exposed to high doses of radiotherapy, and radiationmyocardial fibrosis is usually asymptomatic in the early stageand can be detected at least 10 years after radiotherapy [38]. Inthe late stage of myocardial injury, diffuse myocardial fibrosiscomplicated with severe diastolic dysfunction leads to restric-tive cardiomyopathy [8]. Radiation-induced cardiomyopathycan be characterized by dilated or restricted phenotypes. Buton the whole, radiotherapy-induced cardiomyopathy is morecommon than restrictive cardiomyopathy. The coexistence ofradiation-induced cardiomyopathy and pericardial diseasemay be one of the causes of heart failure [13]. Cardiomyopa-thy is usually characterized by severe signs and symptoms,similar to constrictive pericarditis and severe heart failure.This serious sequela was evident in cases where no improve-ment after pericardiectomy was observed [67].

1.5. Prevention and Treatment of Radiation-InducedCardiotoxicity. Cellular oxidative stress leads to the releaseof toxic free radicals from endothelial cells and vascularsmoothmuscle cells. These active species interact with cellularcomponents, such as proteins, DNA, or lipids, leading toCVD. Therefore, cellular oxidative stress is the main patho-genic factor of CVD [14]. Oxidative stress reflects the imbal-ance between the oxidant and the antioxidant mechanismproduced by the cells, and so the balance needs to be restoredin order to reduce radiation-induced cardiac damage. Antiox-idants are molecules that inhibit oxidative stress chain reac-tions and protect cell components from damage, as shown

in Table 1. They are divided into enzymes and nonenzymeantioxidants. Enzyme antioxidants include SOD, GPX, glu-tathione reductase (GR), and CAT. Nonenzyme antioxidantsbased on their sources include exogenous and intrinsic anti-oxidants. GSH is an endogenous antioxidant; exogenousantioxidants include carotenoids, ascorbic acid (Vit C),α-tocopherol (Vit E), and flavonoids [14]. Antioxidantsare the first line of defense against ROS damage. They canconvert oxidants into less active substances and preventlipids, proteins, and DNA in the cells from being damagedby ROS [25].

1.5.1. Vitamin E. The longest known antioxidant in the bio-logical system is α-tocopherol, which has a relatively highconcentration in the cells and mitochondrial membranes[37]. α-Tocopherol is the most active form of vitamin E(Vit E) [15]. Various sources of food are believed to containa large quantity of vitamin E, especially most of the nutsand seeds, such as almonds, peanuts, and sunflower seeds[70]. A large number of studies have shown that vitamin E,as a powerful antioxidant, has an important impact on car-diovascular events. Vitamin E can regulate the oxidativestress state. For example, α-tocopherol was reported toreduce the production of ROS by reducing the activity ofNADPH oxidase, and Vit E interacted with ascorbic acid(Vit C) to terminate the free radical reaction [19]. Vit E is alsoan anti-inflammatory agent and its major anti-inflammatoryeffect is through the inhibition of NF-κB. The anti-inflammatory effects of α-tocopherol include reducing thesynthesis of ICAM-1 and VCAM-1, downregulating scav-enging receptors, such as CD 36, reducing the release ofIL-1B, and inhibiting the release of IL-1B in monocytes.Therefore, α-tocopherol can inhibit the adhesion of mono-cytes to endothelial cells and reduce their chances of enteringthe subendothelial space [19]. In addition, Vit E provideselectrons to peroxide groups, which are produced in the

Table 1: Antioxidants and their effects.

Antioxidant Source Mechanism Effect

Vitamin EAmygdala, peanut, and sunflower

seeds [70]

Reduce the activity of NADPH oxidase andinhibit lipid peroxidation and downregulate

NF-κB [19]

Antioxidation, anti-inflammation, anda decline of the risk of coronary heart

diseases [75, 76]

Silymarin Milk thistle [77]Stimulate the expression of Nrf2 and

downregulate NF-κB [14]

Suppression of oxidative stress andinflammation and antiatherosclerosis

[14, 80]

Resveratrol Grapes and red wine [81, 82]Reduce the uncoupling of NADPH oxidase and

eNOS and upregulate antioxidant defenseenzymes [81, 82]

Antioxidative and anti-inflammatoryproperties against cardiovascular

diseases [81, 82, 85]

LycopeneTomatoes, watermelons, pinkgrapefruit, apricots, pink guava,

and papaya [29]

Scavenge singlet oxygen, nitrogen dioxide,sulfur, and sulfonyl-free radicals [25]

Prevention of the oxidation of DNA,lipid, and proteins [25, 86]

MelatoninCereals, olives, walnuts, tomatoes,pineapples, ginger, and beans [63]

Donate two electrons directly and stimulatethe enzymatic antioxidant system indirectly

[26, 91]

Suppression of oxidative stress andprevention of RIHD [90, 91]

HesperidinOranges, lemons, grapes, and olive

oil [30]Passivate NADPH oxidase and inhibit TGF-β1

mRNA expression [95]

Inhibition of oxidative stress, cardiachypertrophy, and cardiac remodeling

[95, 96]


process of lipid peroxidation. Therefore, Vit E can reduce therisk of coronary heart disease [14]. Many studies have identi-fied the antioxidant and antiatherosclerotic properties ofvitamin E in animals [71–74]. In 2001, Ferre et al. found thata diet containing vitamin E, palm oil, or sunflower oil wouldreduce the range of pathological changes in the aorta [71].Some observational studies have also shown that a diet withhigher vitamin E content is associated with a lower risk ofcoronary heart disease. In 1993, Rimm et al. found thatmen who took more than 60 IU of vitamin E per day had asignificantly lower risk of coronary heart disease than menwho consumed less than 7.5 IU per day [75]. In addition,men who took 100 IU vitamin E per day for at least 2 yearshad a 37% lower risk of coronary heart disease than menwho did not take vitamin E, according to an observationalstudy [76].

1.5.2. Silymarin. Flavonoids comprise a wide range ofpolyphenolic antioxidants, which can be found in a varietyof fruits and vegetables. Silymarin is one of the polyphenolicflavonoids extracted from milk thistle and belongs to none-nzyme antioxidants [77]. Various animal and human studieshave shown that silymarin and its active components(silybin) exhibit strong antioxidant activities by scavengingfree radicals, increasing glutathione concentration and SODactivity, and inhibiting lipid peroxidation [78, 79]. Silymarin,as an antioxidant, may prevent radiation-induced CVD in avariety of ways. For example, it inhibits ROS-producingenzymes in mitochondria and reduces the production of freeradicals. Silymarin can also upregulate antioxidant enzymesand downregulate the activity of NADPH oxidase in themyocardium by stimulating the expression of Nrf2. Apartfrom the Nrf2 signal pathway, silymarin can also down-regulate the NF-κB pathway to reduce the production ofproinflammatory cytokines and reduce the inflammatoryresponse that stimulates atherosclerosis [14]. In 1999, Mannaet al. showed that silymarin is an effective inhibitor of NF-κBactivation induced by a variety of inflammatory factors.Silymarin can inhibit NF-κB activation by inhibiting thephosphorylation and degradation of IKB [79]. Silymarin, alsoas an herbal antioxidant, is used to prevent CVD, with fewerside effects, and can eliminate ROS and enhance antioxidantenzymes. In addition, Silymarin has a stronger antioxidanteffect than vitamin E and other antioxidants [80].

1.5.3. Resveratrol. Resveratrol is found mainly in grapes andred wine, as well as in plants and fruits, such as peanuts, cran-berries, pistachios, blueberries, and blackberries. It can play apotentially protective role against CVD [81, 82]. Resveratrolis known for its antioxidative and anti-inflammatory proper-ties. The mechanism through which resveratrol protects theheart is by increasing the activity of eNOS, which is beneficialto the generation of NO, the expansion of blood vessels, thereduction of platelet aggregation, and the inhibition of ath-erosclerosis [81]. In recent years, these characteristics havebeen widely studied in animal models and mannequinmodels, both in vivo and in vitro. As an antioxidant, resver-atrol can improve the activity of the antioxidant enzymeand can be used as a free radical scavenger. Therefore, it

can prevent DNA damage and cell membrane lipid peroxida-tion [82]. However, the direct scavenging effect of resveratrolon ROS is relatively poor, and the antioxidant properties ofresveratrol in vivo are more attributed to its role as a redoxgene regulator. It does not just reduce the uncoupling ofNADPH oxidase and eNOS, but it also upregulates antioxi-dant defense enzymes [83]. Recent clinical trials have shownthat resveratrol has low toxicity and good tolerance, and itspharmacological safety is as high as 5 g/day [84]. In 2012,Joao et al. found that dietary interventions supplementedwith resveratrol significantly reduced many cardiac risk fac-tors after 12 months at a low dose (8mg/day) [85].

1.5.4. Lycopene. Many red fruits and vegetables, includingtomatoes, watermelons, pink grapefruit, apricots, pink guava,and papaya contain lycopene [29]. Lycopene is the mosteffective antioxidant among all kinds of common caroten-oids. This carotenoid not only has free radical scavengingactivity, but it also helps maintain the balance of the intracel-lular endogenous antioxidant defense system [25]. Lycopenewas found to scavenge singlet oxygen, nitrogen dioxide, sul-fur, and sulfonyl free radicals. In the process of singlet oxygenquenching, energy is transferred from singlet oxygen to thelycopene molecule and transformed into a triplet state richin energy. The capture of other ROS leads to the oxidativedecomposition of lycopene molecules. In this way, lycopeneprevents the oxidation of lipids, proteins, and DNA in thebody [25, 86]. In 2017, Gajowik and Dobrzyńska reportedthat the effect of adding lycopene one hour before irradiationto protect DNA from oxidative damage was higher than add-ing it immediately before radiation exposure. Moreover, itwas found that the addition of lycopene after radiation couldnot reduce the damage level of DNA. However, lycopenesupplementation, especially at low doses, can be used to pro-tect DNA from radiation-induced oxidative damage [86]. Astudy by Gunasekaran et al. in 2013 also showed that theaddition of lycopene can reduce the level of oxidative stressby inhibiting the formation of ROS and the oxidation ofglutathione [87]. Lycopene was also found to exhibit an anti-cancer activity by reducing cell proliferation induced byinsulin-like growth factor in various cancer cells [25]. There-fore, lycopene seems to be a promising natural antioxidantcandidate for radiation protection and cancer prevention innormal cells [88].

1.5.5. Melatonin. Melatonin is a natural hormone found inplants, such as cereals, olives, walnuts, tomatoes, pineapples,ginger, and beans. Melatonin has a strong radiation protec-tion effect because of its strong antioxidant ability [63]. Dif-ferent animal studies of melatonin in various physiologicand pharmacologic concentrations and representing a widerange of doses have shown that melatonin has very low tox-icity [89]. Melatonin may have protective effects on the heartthrough direct free radical scavenging and indirectly throughits antioxidant properties [90]. The mechanism of melatoninscavenging free radicals seems to be different from most ofthe other antioxidants because melatonin interacts withROS without stimulating the redox system; furthermore,melatonin converts free radicals into stable products, which


basically do not react with other molecules [26]. In addition,the antioxidant effect of melatonin involves the donation oftwo electrons, which do not become free radicals after pro-viding electrons to free radicals and neutralizing free radicalsto protect cells from free radical attacks. In other words, mel-atonin is different from other antioxidants such as vitamin E,because the reaction product of melatonin with free radicalsis an antioxidant in itself [91]. The indirect effect of melato-nin is to stimulate antioxidant defense, including GSH,GPX, SOD, GR, and CAT [92]. Several studies have shownthat melatonin can enhance the activity of glutathione perox-idase and increase the synthesis of glutathione [93]. Melato-nin can also inhibit the translocation of NF-κB into thenucleus, thus inhibiting the signal pathway mediated byNF-κB and protecting the integrity of mitochondria byshielding them from radiation-induced DNA damage, so asto reduce the oxidative stress induced by ROS after radiation[26]. In 2014, Iclal et al. studied the effect of melatonin on theprevention of radiation heart disease in rats by intraperitone-ally injecting 50mg/kg melatonin for 15min before exposureto a single dose of 18Gy. Compared to the untreated group,the histopathological evaluation at 6 months after irradiationshowed that melatonin prevented vasculitis and loweredmuscle cell necrosis and fibrosis [94]. In 2019, Farhoodet al. reported that IL-4 and its downstream genes, IL4ra1,DUOX1, and DUOX2 were activated after rat heart irradia-tion. Melatonin was found to inhibit the increased expressionof IL-4, IL4ra1, DUOX1, and DUOX2 before irradiation andmay have protective effects on heart injury induced by ioniz-ing radiation by inhibiting the expression of IL-4, DUOX1,and DUOX2 [63].

1.5.6. Hesperidin.Hesperidin is a bioflavonoid found in citrusfruits, such as oranges, lemons, and grapes, as well as in plantextracts, such as tea and olive oil. The pericarp of these plantshas the highest concentration of hesperidin. Hesperidin, as anatural antioxidant, has been reported to reduce radiation-induced heart damage [30]. The level of oxidative stress inthe heart of mice fed with hesperidin was significantlydecreased, such as the increased expression of antioxidantenzymes, including SOD1 and SOD2, and passivation ofNADPH oxidase. More importantly, hesperidin plays animportant role in improving cardiac hypertrophy and cardiacremodeling by inhibiting TGF-β1 mRNA expression andSmad2/Smad3 phosphorylation [95]. In 2016, Rezaeyanet al. found that the level of oxidative damage and inflamma-tion were decreased by oral administration of 100mg/kghesperidin for 7 days before a single dose of γ-ray irradiationwith 18Gy in the chest of rats [96]. Compared with irradiatedmice without hesperidin treatment, treatment with hesperi-din in mice for 7 days after radiotherapy significantlydecreased the level of protein carbonyl groups and improvedthe levels of lipid peroxide and glutathione in the heart,which were induced by radiation in a dose-dependentmanner [97]. In addition, it was found that hesperidin couldprotect the heart of aged rats by mediating the expression ofNrf2, upregulating the activity of antioxidant enzymes andreducing the macromolecular damage induced by oxidativestress [98].

2. Limitations and New Research Progresson Antioxidants

Endogenous antioxidants play a crucial role in maintainingoptimal cellular function. However, under oxidative stressconditions, endogenous antioxidants may not be sufficientand the addition of dietary antioxidants may be required.Antioxidant activity depends on some special conditions,particularly the dose in cells and redox conditions of antiox-idants [39]; high doses of antioxidants may alter redoxbalance and lead to cellular dysfunction by interacting withROS at physiological concentration [99]. In the followingarticle, we take vitamin E, melatonin, and resveratrol asexamples. In terms of biological effects, the most active formof vitamin E is α-tocopherol, which is also the most abundantform in nature and has a strong antioxidant effect. Neverthe-less, recent in vitro studies have shown that vitamin E maypromote oxidation at a high dose. A meta-analysis suggeststhat human adults with chronic diseases who consume morethan 400U a day of vitamin E supplements increase all-causemortality [100]. In addition, melatonin has a strong radiationprotection effect owing to its strong antioxidant ability.However, studies have shown that a high concentration ofmelatonin induces intracellular ROSproduction and accumu-lation, exhibiting a prooxidant effect that plays an upstreamrole in mitochondria-mediated apoptosis and autophagy.The results indicate that melatonin at high concentrationwas a potential adjuvant in patients with head and neck squa-mous cell carcinoma who were undergoing radiotherapy[101]. Resveratrol is known for its antioxidant properties,but it has been identified as a cytotoxic and prooxidant com-pound, depending on its concentration, exposure time, andcell type [102]. Although the dose-dependent oxidative effectof resveratrol leads to oxidative stress of cells treated with50ml, the lower cytotoxicity found at 120 h of treatmentmay indicate that the surviving cells seem to bemore resistantto resveratrol-induced oxidative damage, which seems toweaken with the prolongation of treatment time [103]. Tosum up, it is generally accepted that each antioxidant is actu-ally a redox, and therefore, may become a prooxidant, acceler-ating lipid peroxidation and/or inducing DNA damage underspecific conditions. Therefore, it is strongly suggested that thisprooxidant effectmay be an importantmechanism in the anti-cancer effect of resveratrol and induction of apoptosis [102].

3. Conclusions

Accumulating clinical evidence suggests that exposure toionizing radiation increases the risk of CVD. Oxidative stressplays an important role in radiation-induced cardiac toxicity.Oxidative stress is the result of excessive production of ROSand the decrease of ROS scavenging ability. It promotes oxi-dative damage of DNA, which is characterized by cardiacfunction damage. Cancer survivors who initially receivedradiotherapy are at increased risk of multiple manifestationsof CVD. Although modern radiotherapy has adopted cardiacprotection techniques that are likely to reduce the prevalenceand severity of CV complications, more efforts are needed toprevent and treat these side effects. Therefore, in order to


improve the survival rate and prognosis of cancer patientstreated with radiotherapy, the use of natural antioxidants toeliminate excessive ROS, inhibit the production of ROS,and inhibit oxidative stress is a promising strategy for thetreatment of radiation-induced heart disease.

Ethical Approval

All procedures performed in studies involving human partic-ipants were in accordance with the ethical standards of theinstitutional and/or national research committee and withthe 1964 Helsinki declaration and its later amendments orcomparable ethical standards.

Consent

Informed consent was obtained from all individual partici-pants included in the study.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Authors’ Contributions

Cai Xinyong, Yan Peng, Hong Lang, and Shao Liang con-tributed to the conception of the study. Zeng Zhiyi, WuXiaocheng, Zhang Ping, and Shao Liang contributed sig-nificantly to manuscript preparation; Zhang Ping and ShaoLiang performed the reference search and wrote the manu-script; and Cai Xinyong, Yan Peng, Hong Lang, and ShaoLiang helped perform the analysis with constructive discus-sions. Zhang Ping, Yang Peng, and Hong Lang contributedequally to this work.

Acknowledgments

This work was supported by the National Natural ScienceFoundation of China (Grant No. 81300115 to Liang Shao)and the Science and Technology for Public Service ProjectGrants from the Wenzhou Municipal Science and Technol-ogy Bureau (Grant No. Y20150191 to Liang Shao and GrantNo. Y20150114 to Ping Zhang).

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